tbuckley/cabot-search huggingface dataset:
Functional annotation of variants of the BRCA2 gene via locally haploid human pluripotent stem cells
Authors: Hanqin Li, Rebecca Bartke, Lei Zhao, Yogendra Verma, Anna Horacek, Alma Rechav Ben-Natan, Gabriella R. Pangilinan, Netravathi Krishnappa, Rasmus Nielsen, Dirk Hockemeyer
Journal: Nature Biomedical Engineering (2023)

Abstract Mutations in the BRCA2 gene are associated with sporadic and familial cancer, cause genomic instability and sensitize cancer cells to inhibition by the poly(ADP-ribose) polymerase (PARP). Here we show that human pluripotent stem cells (hPSCs) with one copy of BRCA2 deleted can be used to annotate variants of this gene and to test their sensitivities to PARP inhibition. By using Cas9 to edit the functional BRCA2 allele in the locally haploid hPSCs and in fibroblasts differentiated from them, we characterized essential regions in the gene to identify permissive and loss-of-function mutations. We also used Cas9 to directly test the function of individual amino acids, including amino acids encoded by clinical BRCA2 variants of uncertain significance, and identified alleles that are sensitive to PARP inhibitors used as a standard of care in BRCA2 -deficient cancers. Locally haploid human pluripotent stem cells can facilitate detailed structure–function analyses of genes and the rapid functional evaluation of clinically observed mutations.
T cell reactivity to Bordetella pertussis is highly diverse regardless of childhood vaccination
Authors: Ricardo da Silva Antunes, Emily Garrigan, Lorenzo G. Quiambao, Sandeep Kumar Dhanda, Daniel Marrama, Luise Westernberg, Eric Wang, Adam Abawi, Aaron Sutherland, Sandra K. Armstrong, Timothy J. Brickman, John Sidney, April Frazier, Tod J. Merkel, Bjoern Peters, Alessandro Sette
Journal: Cell Host & Microbe (2023)
A single-nucleotide polymorphism in Helicobacter pylori promotes gastric cancer development
Authors: Irshad Sharafutdinov, Nicole Tegtmeyer, Bodo Linz, Manfred Rohde, Michael Vieth, Alfred Chin-Yen Tay, Binit Lamichhane, Vo Phuoc Tuan, Kartika Afrida Fauzia, Heinrich Sticht, Yoshio Yamaoka, Barry J. Marshall, Steffen Backert
Journal: Cell Host & Microbe (2023)
Systematic genomic analysis of SARS-CoV-2 co-infections throughout the pandemic and segregation of the strains involved
Authors: Daniel Peñas-Utrilla, Laura Pérez-Lago, Andrea Molero-Salinas, Agustín Estévez, Amadeo Sanz, Marta Herranz, Carolina Martínez-Laperche, Cristina Andrés-Zayas, Cristina Veintimilla, Pilar Catalán, Roberto Alonso, Patricia Muñoz, Darío García de Viedma, Luis Alcalá, Teresa Aldámiz, Ana Álvarez-Uría, Elena Bermúdez, Emilio Bouza, Sergio Buenestado-Serrano, Almudena Burillo, Raquel Carrillo, Emilia Cercenado, Alejandro Cobos, Cristina Díez, Pilar Escribano, Chiara Fanciulli, Alicia Galar, Mª Dolores García, Paloma Gijón, Helmuth Guillén, Jesús Guinea, Álvaro Irigoyen, Martha Kestler, Juan Carlos López, Marina Machado, Mercedes Marín, Pablo Martín-Rabadán, Pedro Montilla, Belén Padilla, Rosalía Palomino-Cabrera, María Palomo, María Jesús Pérez-Granda, Leire Pérez, Elena Reigadas, Cristina Rincón, Belén Rodríguez, Sara Rodríguez, Cristina Rodríguez-Grande, Adriana Rojas, María Jesús Ruiz-Serrano, Carlos Sánchez, Mar Sánchez, Julia Serrano, Francisco Tejerina, Maricela Valerio, Lara Vesperinas, Teresa Vicente, Sofía de la Villa
Journal: Genome Medicine (2023)

Abstract Background SARS-CoV-2 recombinants involving the divergent Delta and Omicron lineages have been described, and one of them, “Kraken” (XBB.1.5), has recently been a matter of concern. Recombination requires the coexistence of two SARS-CoV-2 strains in the same individual. Only a limited number of studies have focused on the identification of co-infections and are restricted to co-infections involving the Delta/Omicron lineages. Methods We performed a systematic identification of SARS-CoV-2 co-infections throughout the pandemic (7609 different patients sequenced), not biassed towards the involvement of highly divergent lineages. Through a comprehensive set of validations based on the distribution of allelic frequencies, phylogenetic consistency, re-sequencing, host genetic analysis and contextual epidemiological analysis, these co-infections were robustly assigned. Results Fourteen (0.18%) co-infections with ≥ 8 heterozygous calls (8–85 HZs) were identified. Co-infections were identified throughout the pandemic and involved an equal proportion of strains from different lineages/sublineages (including pre-Alpha variants, Delta and Omicron) or strains from the same lineage. Co-infected cases were mainly unvaccinated, with mild or asymptomatic clinical presentation, and most were at risk of overexposure associated with the healthcare environment. Strain segregation enabled integration of sequences to clarify nosocomial outbreaks where analysis had been impaired due to co-infection. Conclusions Co-infection cases were identified throughout the pandemic, not just in the time periods when highly divergent lineages were co-circulating. Co-infections involving different lineages or strains from the same lineage were occurring in the same proportion. Most cases were mild, did not require medical assistance and were not vaccinated, and a large proportion were associated with the hospital environment.
Immune-checkpoint inhibition for resectable non-small-cell lung cancer — opportunities and challenges
Authors: Giannis Mountzios, Jordi Remon, Lizza E. L. Hendriks, Rosario García-Campelo, Christian Rolfo, Paul Van Schil, Patrick M. Forde, Benjamin Besse, Vivek Subbiah, Martin Reck, Jean-Charles Soria, Solange Peters
Journal: Nature Reviews Clinical Oncology (2023)
Reactive oxygen species and nitric oxide scavenging nanoparticles alleviating rheumatoid arthritis through adjusting the seeds and growing soils
Authors: Peng Hua, Ruifeng Liang, Yanbei Tu, Yuying Yin, Man-Kay Law, Meiwan Chen
Journal: Acta Pharmaceutica Sinica B (2023)

Normalizing inﬂamed soils including reactive oxygen species (ROS), nitric oxide (NO), cell-free DNA, and regulating inﬂammation-related seeds such as macrophages, neutrophils, fibroblasts, represent a promising strategy to maintain synovial tissue homeostasis for rheumatoid arthritis (RA) treatment. Herein, ROS scavenging amphiphilic block copolymer PEGylated bilirubin and NO-scavenging PEGylated o-phenylenediamine were fabricated to self-assemble into a dually responsive nanoparticle loaded with JAK inhibitor notopterol (Not@BR/oPDA-PEG, NBOP NPs). The simultaneous ROS and NO depletion combined with JAK-STAT pathway inhibition could not only promote M2 polarization to reduce further ROS and NO generation, but also decrease cytokines and chemokines to prevent immune cell recruitment. Specifically, NBOP NPs responded to high level ROS and NO, and disintegrated to release notopterol in inﬂamed joints as the hydrophobic heads BR and oPDA were transformed into hydrophilic ones. The released notopterol could inhibit the JAK-STAT pathway of inflammatory cells to reduce the secretion of pro-inflammatory cytokines and chemokines. This strategy represented an effective way to regulate RA soils and seeds through breaking the positive feedback loop of inflammation aggravation, achieving an excellent anti-RA efficacy in a collagen-induced arthritis rat model. Taken together, our work offered a reference to adjust RA soils and seeds for enhanced RA treatment.
STK11/LKB1-Deficient Phenotype Rather Than Mutation Diminishes Immunotherapy Efficacy and Represents STING/Type I Interferon/CD8+ T-Cell Dysfunction in NSCLC
Authors: Anlin Li, Yuanyuan Wang, Zhixin Yu, Zihui Tan, Lina He, Sha Fu, Mengting Shi, Wei Du, Linfeng Luo, Zhichao Li, Jiaqing Liu, Yixin Zhou, Wenfeng Fang, Yunpeng Yang, Li Zhang, Shaodong Hong
Journal: Journal of Thoracic Oncology (2023)

Background Conflicting findings have been reported regarding the association between STK11/LKB1 mutations and immune checkpoint inhibitor (ICB) efficacy in NSCLC. It has been demonstrated that tumors could exhibit impaired STK11/LKB1 function even without STK11 mutations. We hypothesized that STK11 deficient phenotype rather than mutation may better stratify ICB outcomes. Methods Selected functional STK11 events and LKB1 protein data were leveraged to establish a transcriptomics-based classifier of STK11 phenotype (STK11 -deficient or -proficient). We analyzed in-house and Genentech/Roche's data of three randomized trials of PD-(L)1 inhibition in NSCLC (ORIENT-11, N=171; OAK, N=699; POPLAR, N=192) and TCGA-NSCLC cohort. Results Tissue STK11 mutation did not affect ICB outcomes. However, the survival benefit of ICB versus chemotherapy lost or reversed in STK11-deficient tumors (HR for death, 95% CI: OAK [0.97, 0.69-1.35]; POPLAR [1.61, 0.88-2.97]; ORIENT-11 [1.07, 0.50-2.29]), while remaining in STK11-proficient tumors (HR for death, 95% CI: OAK [0.81, 0.66-0.99]; POPLAR [0.66, 0.46-0.95]; ORIENT-11 [0.59, 0.37-0.92]). In tumors differentially classified by phenotype and mutation status, STK11-WT/deficient tumors had significantly worse ICB outcomes than STK11-MUT/proficient tumors. The deleterious impact of STK11 deficiency was independent of STK11/KRAS/KEAP1 status or PD-L1 expression. The STING/IFN-I signaling, which was previously shown to be suppressed in STK11-MUT models, was perturbed in patients with STK11-deficient tumors but not in those with STK11-MUT tumors. Surprisingly, while high CD8+ T cell infiltration was significantly associated with prolonged survival with ICB in STK11-proficient tumors, it predicted an opposite trend towards worse ICB outcomes in STK11-deficient tumors across three trials. This suggested an association between STK11 deficiency and CD8+ T cell dysfunction which might not be reversed by PD-(L)1 blockade. Conclusions STK11 phenotype rather than mutation status can accurately distinguish ICB-refractory NSCLC patients and reflect immune suppression. It can help refine stratification algorithm for future clinical research and also provide a reliable resource aiding basic and translational studies in identifying therapeutic targets.
The double‐edged role of neutrophil heterogeneity in inflammatory diseases and cancers
Authors: Wencheng Zhou, Xinran Cao, Qiang Xu, Jiao Qu, Yang Sun
Journal: MedComm (2023)

Neutrophils are important immune cells act as the body's first line of defense against infection and respond to diverse inflammatory cues. Many studies have demonstrated that neutrophils display plasticity in inflammatory diseases and cancers. Clarifying the role of neutrophil heterogeneity in inflammatory diseases and cancers will contribute to the development of novel treatment strategies. In this review, we have presented a review on the development of the understanding on neutrophil heterogeneity from the traditional perspective and a high-resolution viewpoint. A growing body of evidence has confirmed the double-edged role of neutrophils in inflammatory diseases and tumors. This may be due to a lack of precise understanding of the role of specific neutrophil subsets in the disease. Thus, elucidating specific neutrophil subsets involved in diseases would benefit the development of precision medicine. Thusly, we have summarized the relevance and actions of neutrophil heterogeneity in inflammatory diseases and cancers comprehensively. Meanwhile, we also discussed the potential intervention strategy for neutrophils. This review is intended to deepen our understanding of neutrophil heterogeneity in inflammatory diseases and cancers, while hold promise for precise treatment of neutrophil-related diseases.
Disparities in Guideline-Recommended Statin Use for Prevention of Atherosclerotic Cardiovascular Disease by Race, Ethnicity, and Gender
Authors: David A. Frank, Amber E. Johnson, Leslie R.M. Hausmann, Walid F. Gellad, Eric T. Roberts, Ravy K. Vajravelu
Journal: Annals of Internal Medicine (2023)

Although statins are a class I recommendation for prevention of atherosclerotic cardiovascular disease and its complications, their use is suboptimal. Differential underuse may mediate disparities in cardiovascular health for systematically marginalized persons. To estimate disparities in statin use by race-ethnicity-gender and to determine whether these potential disparities are explained by medical appropriateness of therapy and structural factors. Cross-sectional analysis. National Health and Nutrition Examination Survey from 2015 to 2020. Persons eligible for statin therapy based on 2013 and 2018 American College of Cardiology/American Heart Association blood cholesterol guidelines. The independent variable was race-ethnicity-gender. The outcome of interest was use of a statin. Using the Institute of Medicine framework for examining unequal treatment, we calculated adjusted prevalence ratios (aPRs) to estimate disparities in statin use adjusted for age, disease severity, access to health care, and socioeconomic status relative to non-Hispanic White men. For primary prevention, we identified a lower prevalence of statin use that was not explained by measurable differences in disease severity or structural factors among non-Hispanic Black men (aPR, 0.73 [95% CI, 0.59 to 0.88]) and non-Mexican Hispanic women (aPR, 0.74 [CI, 0.53 to 0.95]). For secondary prevention, we identified a lower prevalence of statin use that was not explained by measurable differences in disease severity or structural factors for non-Hispanic Black men (aPR, 0.81 [CI, 0.64 to 0.97]), other/multiracial men (aPR, 0.58 [CI, 0.20 to 0.97]), Mexican American women (aPR, 0.36 [CI, 0.10 to 0.61]), non-Mexican Hispanic women (aPR, 0.57 [CI, 0.33 to 0.82), non-Hispanic White women (aPR, 0.69 [CI, 0.56 to 0.83]), and non-Hispanic Black women (aPR, 0.75 [CI, 0.57 to 0.92]). Cross-sectional data; lack of geographic, language, or statin-dose data. Statin use disparities for several race-ethnicity-gender groups are not explained by measurable differences in medical appropriateness of therapy, access to health care, and socioeconomic status. These residual disparities may be partially mediated by unobserved processes that contribute to health inequity, including bias, stereotyping, and mistrust. National Institutes of Health.
Global Comparison of Readmission Rates for Patients With Heart Failure
Authors: Farid Foroutan, Daniel G. Rayner, Heather J. Ross, Tamara Ehler, Ananya Srivastava, Sheojung Shin, Abdullah Malik, Harsukh Benipal, Clarissa Yu, Tsz Hin Alexander Lau, Joshua G. Lee, Rodolfo Rocha, Peter C. Austin, Daniel Levy, Jennifer E. Ho, John J.V. McMurray, Faiez Zannad, George Tomlinson, John A. Spertus, Douglas S. Lee
Journal: Journal of the American College of Cardiology (2023)
Postapproval Study of a Subcutaneous Implantable Cardioverter-Defibrillator System
Authors: Michael R. Gold, Mikhael F. El-Chami, Martin C. Burke, Gaurav A. Upadhyay, Mark J. Niebauer, Jordan M. Prutkin, John M. Herre, Steven Kutalek, Jay L. Dinerman, Bradley P. Knight, Jill Leigh, Lindsay Lucas, Nathan Carter, Amy J. Brisben, Johan D. Aasbo, Raul Weiss
Journal: Journal of the American College of Cardiology (2023)

The subcutaneous implantable cardioverter-defibrillator (S-ICD) was developed to avoid complications related to transvenous implantable cardioverter-defibrillator (TV-ICD) leads. Device safety and efficacy were demonstrated previously with atypical clinical patients or limited follow-up. The S-ICD PAS (Subcutaneous Implantable Cardioverter-Defibrillator System Post Approval Study) is a real-world, multicenter, registry of U.S. centers that was designed to assess long-term S-ICD safety and efficacy in a diverse group of patients and implantation centers. Patients were enrolled in 86 U.S. centers with standard S-ICD indications and were observed for up to 5 years. Efficacy endpoints were first and final shock efficacy. Safety endpoints were complications directly related to the S-ICD system or implantation procedure. Endpoints were assessed using prespecified performance goals. A total of 1,643 patients were prospectively enrolled, with a median follow-up of 4.2 years. All prespecified safety and efficacy endpoint goals were met. Shock efficacy rates for discrete episodes of ventricular tachycardia or ventricular fibrillation were 98.4%, and they did not differ significantly across follow-up years (P = 0.68). S-ICD–related and electrode-related complication-free rates were 93.4% and 99.3%, respectively. Only 1.6% of patients had their devices replaced by a TV-ICD for a pacing need. Cumulative all-cause mortality was 21.7%. In the largest prospective study of the S-ICD to date, all study endpoints were met, despite a cohort with more comorbidities than in most previous trials. Complication rates were low and shock efficacy was high. These results demonstrate the 5-year S-ICD safety and efficacy for a large, diverse cohort of S-ICD recipients. (Subcutaneous Implantable Cardioverter-Defibrillator [S-ICD] System Post Approval Study [PAS]; NCT01736618)
How Canada’s decentralised covid-19 response affected public health data and decision making
Authors: Tania Bubela, Colleen M Flood, Kimberlyn McGrail, Sharon E Straus, Sharmistha Mishra
Journal: BMJ (2023)

Canada's public health system was reformed after its 2003 severe acute respiratory syndrome (SARS) outbreak, which was the worst outside of Asia with 438 cases and 44 deaths. 1 Ensuing national and provincial inquiries led to the creation of the national Public Health Agency of Canada (PHAC) to coordinate Canada's preparation for and response to public health threats. 2 Subnational public health agencies were also created or strengthened to function as regional centres for disease control. 1 These actions should have put Canada in a good position to respond to the covid-19 pandemic. 3 4Despite these reforms, Canada experienced serious failures during the covid-19 pandemic.Memories faded rapidly after SARS, and if history is not to repeat itself, government and health system leaders must strengthen the country's public health and healthcare systems in preparation for the next threat.Health authorities as well as all Canadians need to reflect on the crises of the past three years-what went well and why; what caused pandemic response failures, and what were their consequences?Here, in the first of a series of articles examining Canada's response and setting out suggestions for a national inquiry, we examine the limitations of the country's decentralised structure for public health decision making and missed lessons from the 2003 SARS-CoV-1 outbreak, particularly with regard to data infrastructure. 5Other articles in the series examine how research and data failed to inform public health responses tailored to community and population needs, 6 the predictable failures in long term care, 7 and Canada's role in global vaccine inequity.
Molecular Classification Predicts Response to Radiotherapy in the Randomized PORTEC-1 and PORTEC-2 Trials for Early-Stage Endometrioid Endometrial Cancer
Authors: Nanda Horeweg, Remi A. Nout, Ina M. Jürgenliemk-Schulz, Ludy C.H.W. Lutgens, Jan J. Jobsen, Marie A.D. Haverkort, Jan Willem M. Mens, Annerie Slot, Bastiaan G. Wortman, Stephanie M. de Boer, Ellen Stelloo, Karen W. Verhoeven-Adema, Hein Putter, Vincent T.H.B.M. Smit, Tjalling Bosse, Carien L. Creutzberg, C.L. Creutzberg, P.C.M. Koper, W.L.J. van Putten, R. Dercksen, M. van Lent, H. Beerman, M.L.M. Lybeert, J.J. Jobsen, J.H. Meerwaldt, C.C. Wárlám-Rodenhuis, K.A.J. De Winter, L.C.H.W. Lutgens, A.C.M. van den Bergh, E.M. van de Steen-Banasik, M.C. Stenfert Kroese, L.A.M. Pop, L. Uitterhoeve, A.A. Snijders-Keilholz, B.N.F.M. van Bunningen, J.H. Biesta, F.M. Gescher, J. Pomp, O.W.M. Meijer, J.H. Tabak, A. Slot, I.M. Jürgenliemk-Schulz, E.M. van der Steen-Banasik, J.W.M. Mens, R.A. Nout, V.T.H.B.M. Smit, J.W. Leer, P.R. Timmer, B. van Triest, B. Pras, R. Wiggenraad, F. Gescher, V.L.M. Coen
Journal: Journal of Clinical Oncology (2023)

The molecular classification of endometrial cancer (EC) has proven to have prognostic value and is predictive of response to adjuvant chemotherapy. Here, we investigate its predictive value for response to external beam radiotherapy (EBRT) and vaginal brachytherapy (VBT) in early-stage endometrioid EC (EEC).Data of the randomized PORTEC-1 trial (n = 714) comparing pelvic EBRT with no adjuvant therapy in early-stage intermediate-risk EC and the PORTEC-2 trial (n = 427) comparing VBT with EBRT in early-stage high-intermediate-risk EC were used. Locoregional (including vaginal and pelvic) recurrence-free survival was compared between treatment groups across the four molecular classes using Kaplan-Meier's methodology and log-rank tests.A total of 880 molecularly classified ECs, 484 from PORTEC-1 and 396 from PORTEC-2, were included. The majority were FIGO-2009 stage I EEC (97.2%). The median follow-up was 11.3 years. No locoregional recurrences were observed in EC with a pathogenic mutation of DNA polymerase-ε (POLEmut EC). In mismatch repair-deficient (MMRd) EC, locoregional recurrence-free survival was similar after EBRT (94.2%), VBT (94.2%), and no adjuvant therapy (90.3%; P = .74). In EC with a p53 abnormality (p53abn EC), EBRT (96.9%) had a substantial benefit over VBT (64.3%) and no adjuvant therapy (72.2%; P = .048). In EC with no specific molecular profile (NSMP EC), both EBRT (98.3%) and VBT (96.2%) yielded better locoregional control than no adjuvant therapy (87.7%; P < .0001).The molecular classification of EC predicts response to radiotherapy in stage I EEC and may guide adjuvant treatment decisions. Omitting radiotherapy seems to be safe in POLEmut EC. The benefit of radiotherapy seems to be limited in MMRd EC. EBRT yields a significantly better locoregional recurrence-free survival than VBT or no adjuvant therapy in p53abn EC. VBT is the treatment of choice for NSMP EC as it is as effective as EBRT and significantly better than no adjuvant therapy for locoregional tumor control.
SGLT2 inhibitors alleviated podocyte damage in lupus nephritis by decreasing inflammation and enhancing autophagy
Authors: Xin-yu Zhao, Shuang-shuang Li, Ying-xin He, Li-jie Yan, Fu Lv, Qi-meng Liang, Yu-hui Gan, Li-pei Han, Hong-de Xu, Yong-chun Li, Yuan-yuan Qi
Journal: Annals of the Rheumatic Diseases (2023)

The protective role of sodium glucose cotransporter 2 (SGLT2) inhibitors in renal outcomes has been revealed by large cardiovascular outcome trials among patients with type 2 diabetes. However, the effect of SGLT2 inhibitors on lupus nephritis (LN) and its underlying mechanisms remain unknown.We applied empagliflozin treatment to lupus-prone MRL/lpr mice to explore the renal protective potential of SGLT2 inhibitors. An SGLT2 knockout monoclonal podocyte cell line was generated using the CRISPR/Cas9 system to examine the cellular and molecular mechanisms.In MRL/lpr mice treated with empagliflozin, the levels of mouse anti-dsDNA IgG-specific antibodies, serum creatinine and proteinuria were markedly decreased. For renal pathology assessment, both the glomerular and tubulointerstitial damages were lessened by administration of empagliflozin. The levels of SGLT2 expression were increased and colocalised with decreased synaptopodin in the renal biopsy samples from patients with LN and MRL/lpr mice with nephritis. The SGLT2 inhibitor empagliflozin could alleviated podocyte injury by attenuating inflammation and enhanced autophagy by reducing mTORC1 activity. Nine patients with LN treated with SGLT2 inhibitors with more than 2 months of follow-up showed that the use of SGLT2 inhibitors was associated with a significant decrease in proteinuria from 29.6% to 96.3%. Moreover, the estimated glomerular filtration rate (eGFR) was relatively stable during the treatment with SGLT2 inhibitors.This study confirmed the renoprotective effect of SGLT2 inhibitors in lupus mice, providing more evidence for non-immunosuppressive therapies to improve renal function in classic autoimmune kidney diseases such as LN.